This invention relates to a composition for treating or preventing glomerulopathy, especially glomerulonephritis and diabetic nephropathy, having a superior antiproteinuric effect and to a novel compound having superior inhibitory activity for type IV collagenase and an antiproteinuric effect and a composition containing it for treating or preventing.
A glomerulus is organized by epithelial cells, mesangial cells, endothelial cells, and epithelial cells of Bowman""s capsule. The glomerulus filtrates blood to produce a glomerular filtrate containing substantially the same components as plasma components of which molecular weight is 10,000 or less. Generally, the filtration is controlled not to leak essential substances in blood, especially serum protein, to urine.
Glomerulus damage causes the growth of mesangial cells which are one of the glomerulus component cells and the expansion of a neighbor extracellular matrix to increase the amount of urinary protein excretion. It is known that the increase of urinary protein excretion further lowers the renal function by leading glomerulopathy to damage of renal tubules. Therefore, the inhibition of the urinary protein excretion is expected to improve various diseases associated with glomerulopathy. Such damage is derived from not only a primary disease but also a systemic disease such as diabetes. However, initiation and progression mechanisms remain uncertain and a fundamental method for treatment is not established.
As the present treating method, symptomatic therapies are carried out, but they have many problems. For example, the immunosuppressants are used for patients of nephritis because many types of nephritis are considered to be caused by immunologic mechanism, but nephrotoxicity occurs by the prolonged administration. Though steroids are also administered to the patients of nephritis, some nephritis are resistant to them. Recently, it is proved that angiotensin converting enzyme inhibitors (antihypertensive agents) are useful for nephritis. However, the medicament for nephritis without a hypotensive effect is required.
Accordingly, pharmacotherapy of glomerulopathy has been in a trial and error stage. The treatment of glomerulopathy is made more difficult by the fact that the cause of glomerulopathy is not all alike and clinical course full of variety can not easily be prospected.
As a treating agent for nephritis other than the above mentioned medicament, compounds described in JP-A-9-87176 are exemplified.
Compounds similar to those of the present invention are described in WO97/27174, EP0757984 A1, EP0757037 A2, WO97/45402, WO97/44315, WO96/00214, WO95/35276, and WO97/05865.
In the above situation, the inventors of the present invention have studied on the medicament which can inhibit the initiation and progression of glomerulopathy such as glomerulonephritis and diabetic nephropathy or decrease urinary protein excretion.
The inventors of the present invention made glomerulopathy model rats which leak urine proteins by using a nephritogenic antibody and searched for compounds inhibiting the initiation and progression of the damage of model rats. In result, the inventors of the present invention found that some sulfonamide derivatives inhibited the initiation and progression of glomerulopathy, especially glomerulonephritis and diabetic nephropathy through the inhibition of protein excretion and they are useful treating or preventing them.
The present invention relates to i) to xxxiv) represented below.
i) A composition for treating or preventing glomerulopathy which contains a compound of the formula (I): 
wherein R1 and R2 are each independently hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroayl, or optionally substituted heteroarylalkyl;
R3 is 1,4-phenylene or 2,5-thiophendiyl;
R4 is a substituent represented by the formula: 
wherein R5 is hydrogen atom, hydroxy, optionally substituted lower alkyloxy, mercapto, lower alkylthio, cycloalkyl, halogen, carboxy, lower alkyloxycarbonyl, nitro, cyano, lower holoalkyl, aryloxy, optionally substituted amino, guanidino, optionally substituted lower alkyl, lower alkenyl, lower alkynyl, acyl, acyloxy, xe2x80x94CONRARB, xe2x80x94N(RC)CORD (wherein RA, RB, and RC are the same or different selected from hydrogen atom, lower alkyl, or aralkyl; RD is lower alkyl, aryl, and aralkyl), optionally substituted non-aromatic heterocyclic group, or optionally substituted heteroaryl;
R6 is optionally substituted lower alkyl, cycloalkyl, lower alkyloxy, halogen, lower alkylthio, optionally substituted amino, carboxy, lower alkyloxycarbonyl, aryloxy, phenyl, optionally substituted non-aromatic heterocyclic group, or optionally substituted heteroaryl; and
Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
ii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (II): 
wherein R1, R2, and R3 are as defined above:
R7 is a substitution represented by the formula: 
wherein R8 is hydrogen atom, hydroxy, lower alkyloxy, mercapto, lower alkylthio, cycloalkyl, halogen, carboxy, lower alkyloxycarbonyl, nitro, cyano, lower haloalkyl, aryloxy, optionally substituted amino, guanidino, optionally substituted lower alkyl, lower alkenyl, lower alkynyl, alkanoyl, acyloxy, or optionally substituted heteroaryl;
R9 is optionally substituted lower alkyl, cycloalkyl, carboxy, lower alkyloxycarbonyl, aryloxy, or phenyl; and
Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
iii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (I): 
wherein R1, R2, and R3 are as defined above;
R4 is a substituent represented by the formula: 
wherein R10 is hydrogen atom, optionally substituted lower alkyloxy, lower alkylthio, halogen, optionally substituted amino, optionally substituted lower alkyl, or optionally substituted non-aromatic heterocyclic group;
R11 is optionally substituted lower alkyl, lower alkylthio, halogen, optionally substituted amino, phenyl, optionally substituted non-aromatic heterocyclic group, or optionally substituted heteroaryl; and
Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
iv) A composition for treating or preventing glomerulopathy which contains a compound of the formula (II): 
wherein R1, R2, and R3 are as defined above;
R7 is a substituent represented by the formula: 
wherein R12 is hydrogen atom, halogen, nitro, optionally substituted lower alkyl, lower alkyloxy, or lower alkylthio;
R13 is optionally substituted lower alkyl or phenyl; and
Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
v) A composition for treating or preventing glomerulopathy which contains a compound of the formula (III): 
wherein R1, R10, and Y are as defined above; and R14 is hydrogen atom or lower alkyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
vi) A composition for treating or preventing glomerulopathy which contains a compound of the formula (IV): 
wherein R1, R12, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
vii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (V): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
viii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (VI): 
wherein R1, R12, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
ix) A composition for treating or preventing glomerulopathy which contains a compound of the formula (VII): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
x) A composition for treating or preventing glomerulopathy which contains a compound of the formula (VIII): 
wherein R1, R12, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
xi) A composition for treating or preventing glomerulopathy which contains a compound of the formula (IX): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (X): 
wherein R1, R12, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
xiii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (XI): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
xiv) A composition for treating or preventing glomerulopathy which contains a compound of the formula (XII): 
wherein R1, R12, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
xv) A composition for treating or preventing glomerulopathy which contains a compound of the formula (XIII): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xvi) A composition for treating or preventing glomerulopathy which contains a compound of the formula (XIV): 
wherein R1, R12, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xvii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (XV): 
wherein R1, R11, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
xviii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (XVI): 
wherein R1, R13, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xix) The composition for treating or preventing glomerulopathy of any one of above i) to
xviii), wherein RI is hydrogen atom, methyl, i-propyl, i-butyl, optionally substituted benzyl, optionally substituted indol-3-ylmethyl, or phenylaminocarbonylethyl.
xx) The composition for treating or preventing glomerulopathy of any one of above i) to xviii), wherein R1 is i-propyl, benzyl, or indol-3-ylmethyl.
xxi) The composition for treating or preventing glomerulopathy of any one of above i) to xx), wherein R2 and R14 are hydrogen atom.
xxii) The composition for treating or preventing glomerulopathy of any one of above i) to xxi), wherein Y is OH.
xxiii) The composition for treating or preventing glomerulopathy of any one of above i) to xxii), wherein glomerulopathy is glomerulonephritis.
xxiv) The composition for treating or preventing glomerulopathy of any one of above i) to xxii), wherein glomerulopathy is diabetic nephropathy.
xxv) A compound of the formula (XVII): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xxvi) A compound of the formula (XVIII): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xxvii) A compound of the formula (XIX): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xxviii) A compound of the formula (XX): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xxix) A compound of the formula (XX): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xxx) A compound of the formula (XXII): 
wherein R1, R10, R14, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xxxi) A compound of the formula (XXIII): 
wherein R1, R10, R14 and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xxxii) A pharmaceutical composition containing a compound of any one of above xxv) to xxxi).
xxxiii) A composition for inhibiting matrix metalloproteinase containing a compound of any one of above xxv) to xxxi).
xxxiv) A composition for inhibiting type IV collagenase containing a compound of any one of above xxv) to xxxi).
xxxv) A composition for treating or preventing glomerulopathy which contains a compound of any one of above xxv) to xxxi).
xxxvi) A composition for treating or preventing glomerulopathy which contains a compound of the formula (XXIV): 
wherein the combination of each substituent is represented below, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
xxxvii) A composition for treating or preventing glomerulopathy which contains a compound of the formula (XXIV): 
wherein the combination of each substituent is represented below, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
xxxviii) The composition for treating or preventing glomerulopathy of any one of above xxxv) to xxxvii), wherein glomerulopathy is glomerulonephritis.
xxxix) The composition for treating or preventing glomerulopathy of any one of above xxxv) to xxxvii), wherein glomerulopathy is diabetic nephropathy.
Among the above mentioned compounds with superior activity for treating or preventing glomerulopathy, preferred are shown below.
Compound No.: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 23, 24, 26, 28, 29, 31, 32, 33, 34, 35, 39, 40, 41, 44, 48, 51, 52, 54, 55, 56, 57, 59, 61, 62, 73, 81, 82, 84, 86, 91, 92, 93, 94, 95, 97, 98, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 112, 113, 114, 115, 119, 120, and 121.
More preferred compounds are No.: 1, 2, 3, 4, 5, 6, 7, 9, 12, 13, 15, 16, 17, 18, 19, 22, 29, 31, 32, 33, 34, 35, 39, 51, 54, 55, 56, 57, 59, 61, 62, 80, 82, 84, 86, 91, 92, 92, 94, 95, 96, 97, 101, 108, 112, 113, 115, 119, 120, and 121.
Most preferred compounds are No.: 1, 2, 4, 7, 9, 12, 15, 16, 17, 18, 19, 23, 31, 33, 32, 34, 39, 54, 56, 57, 61, 62, 80, 84, 86, 91, 92, 95, 97, 101, 108, and 121.
The term xe2x80x9cglomerulopathyxe2x80x9d herein used means dysfunction of glomerulus or change of form of glomerulus caused by an endogenous or exogenous factor.
The term xe2x80x9cglomerulonephritisxe2x80x9d herein used means renal dysfunction derived from glomerulus dysfunction which is caused by a hereditary or exogenous factor or autoimmune disorder. This term includes nephrosis such as membranous nephropathy without inflammatory response.
The term xe2x80x9cdiabetic nephropathyxe2x80x9d herein used means all renal dysfunction observed after crisis of diabetes.
The term xe2x80x9clower alkylxe2x80x9d herein used means C1 to C6 straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. C1 to C4 alkyl is preferred.
The term xe2x80x9ccycloalkylxe2x80x9d herein used are exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term xe2x80x9carylxe2x80x9d herein used means monocyclic or condensed ring aromatic hydrocarbons. Examples of the aryl are phenyl, 1-naphthyl, 2-naphthyl, and the like.
The term xe2x80x9caralkylxe2x80x9d herein used means the above mentioned xe2x80x9clower alkylxe2x80x9d substituted with the above mentioned xe2x80x9carylxe2x80x9d at any possible position. Examples of the aralkyl are benzyl, phenethyl (2-phenethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl), anthrylmethyl (e.g., 9-anthrylmethyl), and the like. Benzyl is preferred.
The term xe2x80x9cheteroarylxe2x80x9d herein used means a 5 to 6 membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and may be fused with the above mentioned xe2x80x9carylxe2x80x9d, xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d, and other xe2x80x9cheteroarylxe2x80x9d at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 3-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isooxazolyl (e.g., 3-isooxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like. Indolyl, pyrazolyl, and pyridyl are preferred.
The term xe2x80x9cheteroarylalkylxe2x80x9d herein used means the above mentioned xe2x80x9clower alkylxe2x80x9d substituted with the above mentioned xe2x80x9cheteroarylxe2x80x9d at any possible position. Examples of the heteroarylalkyl are thiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g., 5-thiazolyl-2-ethyl), indolylmethyl (e.g., indol-3-ylmethyl), imidazolylmethyl (e.g., 4-imidazolylmethyl), benzothiazolylmethyl (e.g., 2-benzothiazolylmethyl), benzopyrazolylmethyl (e.g., 1-benzopyrazolylmethyl), benzotriazolylmethyl (e.g., 4-benzotriazolylmethyl), benzoquinolylmethyl (e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g., 2-benzimidazolylmethyl), pyridylmethyl (e.g., 2-pyridylmethyl), and the like. As a preferred heteroarylalkyl, indol-3-ylmethyl is exemplified.
The term xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d herein used means a 5 to 7 membered non-aromatic ring which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and condensed ring which are fused with two or more themselves. Examples of the non-aromatic heterocyclic group are pyrrolidine, piperidine, piperazine, octahydroquinoline, tetrahydrofuran, tetrahydropyrane, morpholine, and the like. Pyrrolidine and morpholine are preferred.
The term xe2x80x9clower alkyloxyxe2x80x9d herein used means alkyloxy of which alkyl part is the above mentioned lower alkyl. Examples of the lower alkyloxy are methyloxy, ethyloxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy, tert-butyloxy, and the like. C1 to C4 alkyloxy is preferred.
The term xe2x80x9chalogenxe2x80x9d herein used means fluoro, chloro, bromo, and iodo. Fluoro, chloro, and bromo are preferred.
The term xe2x80x9clower alkylthioxe2x80x9d herein used means alkylthio of which alkyl part is the above mentioned xe2x80x9clower alkylxe2x80x9d. Examples of the lower alkylthio are methylthio, ethylthio, and the like.
The term xe2x80x9clower alkyloxycarbonylxe2x80x9d herein used means lower alkyloxycarbonyl of which alkyloxy part is the above mentioned xe2x80x9clower alkyloxyxe2x80x9d. Examples of the lower alkyloxycarbonyl are methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, and the like.
The term xe2x80x9clower haloalkylxe2x80x9d herein used means the above mentioned xe2x80x9clower alkylxe2x80x9d which is substituted with the above mentioned xe2x80x9chalogenxe2x80x9d at 1 to 5 positions. Examples of the lower haloalkyl are trichloromethyl, trichloroethyl, trifluoromethyl, trifluoroethyl, and the like.
The term xe2x80x9caryloxyxe2x80x9d herein used means aryloxy of which aryl part is the above mentioned xe2x80x9carylxe2x80x9d. Examples of the aryloxy are phenyloxy and the like.
The term xe2x80x9clower alkenylxe2x80x9d herein used means C2 to C6 straight or branched chain alkenyl. Examples of the lower alkenyl are vinyl, allyl, propenyl, butenyl, and the like.
The term xe2x80x9clower alkynylxe2x80x9d herein used means C2 to C8 straight or branched chain alkynyl. Examples of the lower alkynyl are ethynyl, 1-propynyl, propargyl, 1-hexynyl, and the like.
The term xe2x80x9cacylxe2x80x9d herein used means alkanoyl of which carbonyl is bonded to the above mentioned xe2x80x9clower alkylxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d and aroyl of which carbonyl is bonded to the above mentioned xe2x80x9carylxe2x80x9d. Examples of the acyl are acetyl, n-propanoyl, isopropanoyl, n-butyloyl, t-butyloyl, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, benzoyl, and the like. Acetyl and benzoyl are preferred.
The term xe2x80x9calkanoylxe2x80x9d herein used means alkanoyl of which carbonyl is bonded to the above mentioned xe2x80x9clower alkylxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d. Examples of the alkanoyl are acetyl, n-propanoyl, isopropanoyl, n-butyloyl, t-butyloyl, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, and the like. Acetyl is preferred.
The term xe2x80x9cacyloxyxe2x80x9d herein used means acyloxy of which oxygen atom is bonded directly to the above mentioned xe2x80x9cacylxe2x80x9d. Examples of the acyloxy are acetyloxy, n-propanoyloxy, isopropanoyloxy, n-butyloyloxy, t-butyloyloxy, cyclopropanoyloxy, cyclobutanoyloxy, cyclopentanoyloxy, cyclohexanoyloxy, benzoyloxy, xcex1-naphthoyloxy, xcex2-naphthoyloxy, and the like.
The term xe2x80x9coptionally substituted aminoxe2x80x9d herein used means amino substituted with one, two, or more of the above mentioned xe2x80x9clower alkylxe2x80x9d, xe2x80x9caralkylxe2x80x9d, or xe2x80x9cheteroarylalkylxe2x80x9d or non-substituted. Examples of the optionally substituted amino are amino, methylamino, dimethylamino, ethylmethylamino, diethylamino, benzylamino, and the like.
The substituents of xe2x80x9coptionally substituted alkylxe2x80x9d for R1 and R2 are hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, lower alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, lower haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), optionally substituted carbamoyl (e.g., phenylcarbamoyl), guanidino, phenyl, benzyloxy, and the like. These substituents are able to bind to it at one or more of any possible positions.
Examples of xe2x80x9coptionally substituted alkylxe2x80x9d of R1 and R2 are methyl, ethyl, n-propyl, i-propyl, i-butyl, phenylcarbamoylethyl, methylthioethyl, and the like.
The substituents for xe2x80x9coptionally substituted alkylxe2x80x9d of R5, R6, R12, and R13 are optionally protected hydroxy (e.g., hydroxy, methylsulfonyloxy, and p-toluenesulfonyloxy), alkyloxy (e.g., methyloxy, ethyloxy, n-propyloxy, and u-butyloxy), azide, mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, lower alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, lower haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), guanidino, phenyl, benzyloxy, and the like. These substituents are able to bind to it at one or more of any possible positions. Preferred substituents are optionally protected hydroxy, azide, halogen, and optionally substituted amino.
Examples of xe2x80x9coptionally substituted alkylxe2x80x9d of R5, R6, R12, and R13 are methyl, ethyl, n-propyl, i-propyl, n-butyl, hydroxymethyl, 2-hydroxyethyl, 2-ehtylazide, trifluoromethyl, and the like.
The substituents for xe2x80x9coptionally substituted alkylxe2x80x9d of R8, R9, R12, and R13 are optionally protected hydroxy (e.g., hydroxy, methylsulfonyloxy, and p-toluenesulfonyloxy), alkyloxy (e.g., methyloxy and ethyloxy), azide, mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, lower alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, lower haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), guanidino, phenyl, benzyloxy, and the like. These substituents are able to bind to it at one or more of any possible positions. Preferred substituents are optionally protected hydroxy, azide, halogen, and optionally substituted amino.
Examples of the substituents of xe2x80x9coptionally substituted alkyloxyxe2x80x9d herein used are optionally substituted amino (amino, methylamino, dimethylamino, ethylamino, ethylmethylamino, and diethylamino), and the like. Preferred is optionally substituted amino.
Examples of xe2x80x9coptionally substituted alkyloxyxe2x80x9d are methyloxy, ethyloxy, n-propyloxy, n-butyloxy, 3-dimethylaminopropyloxy, and the like.
Substituents on the aromatic ring of xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted aralkylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, and xe2x80x9coptionally substituted heteroarylalkylxe2x80x9d are, for example, hydroxy, lower alkoxy (e.g., methyloxy and ethyloxy), mercapto, lower alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, lower alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, lower haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy), optionally substituted amino (e.g., methylamino, dimethylamino, diethylamino, and benzylidenamino), guanidino, lower alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, and tert-pentyl), lower alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), lower alkanoyl (e.g., formyl, acetyl, and propionyl), acyloxy (e.g., acetyloxy), acylamino, lower alkylsulfonyl (e.g., methylsulfonyl), phenyl, benzyl, an azo group (e.g., phenylazo), optionally substituted heteroaryl (e.g., 3-pyridyl), optionally substituted ureido (e.g., ureido and phenylureido), and the like. These substituents are able to bind to it at one or more of any possible positions.
The examples of the substituents for xe2x80x9coptionally substituted non-aromatic heterocyclic groupxe2x80x9d are lower alkyl (e.g., methyl, ethyl, n-propyl, and i-propyl) and the like.
The examples of xe2x80x9coptionally substituted non-aromatic heterocyclic groupxe2x80x9d are 1-pyrrolidinyl, morpholino, piperidino, oxazolidino, and the like.